Israeli Researchers Study Positive Impact of Cannabis Oil in Treatment of Autism
by Sharon Wrobel
Prof. Daniel Offen of the Sackler Faculty of Medicine at Tel Aviv University (Credit: Tel Aviv University)
Research by Israeli scientists suggests medical cannabis oil could be “effective” in alleviating compulsive and anxious behaviors of autism, according to an initial study of animal models.
According to the results of the research, led by Prof. Daniel Offen and PhD student Shani Poleg of Tel Aviv University’s Sackler Faculty of Medicine, one of the two compounds of cannabis was found to be more effective in the treatment of autism mice.
The researchers reported that they were “surprised” to find that treatment with cannabis oil that contains the tetrahydrocannabinol (THC) substance of the hemp plant showed better impact.
“Clinical trials testing cannabis treatments for autism usually involve strains containing very large amounts of CBD [cannabidiol] — due to this substance’s anti-inflammatory properties, and because it does not produce a sense of euphoria. Moreover, the strains used for treating autism usually contain very little THC, due to apprehension regarding both the euphoria and possible long-term effects,” Poleg explained. “In the second stage of our study we inquired which active substance in cannabis causes the behavioral improvement, and were surprised to discover that treatment with cannabis oil that contains THC but does not contain CBD produces equal or even better effects — both behavioral and biochemical.”
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Autism is a neurodevelopmental disorder, and its main symptoms are social deficiencies and compulsive behaviors. Prof. Offen noted that since cannabis is not defined as a medication, trials have already been conducted in children and adolescents with autism without any preliminary studies, which at times has led to misinformation on the treatment.
“According to the prevailing theory, autism involves over-arousal of the brain, which causes compulsive behavior,” Poleg said. “In the lab, in addition to the behavioral results, we saw a significant decrease in the concentration of the arousing neurotransmitter glutamate in the spinal fluid — which can explain the reduction in behavioral symptoms.”
Additionally, the study suggested that CBD alone has no impact on the behavior of autism in mice, Poleg added.
Against this, the researchers observed “significant” improvement in behavioral tests following treatments with cannabis oil containing small amounts of THC. There were no long-term effects reported in cognitive or emotional tests conducted a month and a half after treatment start. The mutation, called Shank3, that caused autism in the study’s animal model is responsible for about one percent of all autism cases, the study said.
“This is of course an initial study,” Poleg stated. “But we hope that through our basic research we will be able to improve clinical treatments. Our study shows that when treating autism with medicinal cannabis oil there is no need for high contents of either CBD or THC.”
The study results were published in Translational Psychology published by Nature.
Autism Spectrum Disorder
Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders, the symptoms of which include impaired communication and social interaction with restricted or repetitive motor movements. In some instances, it may also be associated with general cognitive deficits. Although ASD can be diagnosed at any age, it is defined as a “developmental disorder” because symptoms typically manifest within the first two years of life. Autism is known as a spectrum disorder because its symptoms can range from mild to debilitating.
Modulation of the endocannabinoid system has been suggested as a target for ASD therapies,  and children with ASD have been found to possess lower-than-normal levels of certain endogenous cannabinoids, including anandamide. 
In recent years, a growing number of human studies and case reports have documented improvements in ASD patients following the administration of various cannabinoid formulations. 
For instance, a 2019 Brazilian observational trial reported that the twice-daily administration of plant-derived CBD extracts was associated with improved ASD symptoms in 14 out of 15 adolescent subjects. 
A series of Israeli trials have also documented favorable results. In 2018, researchers reported to the journal Neurology that the administration of CBD-dominant cannabis extracts led to significant improvements in over 60 percent of ASD patients with refractory behavioral problems. 
A 2019 study involving 188 patients reported that over 90 percent of subjects who were administered CBD-dominant extracts for a period of at least six months demonstrated “some level of symptomatic improvement.” Approximately one-third of respondents reported a reduction in their intake of other medications. Authors concluded, “Cannabis as a treatment for autism spectrum disorders patients appears to be well-tolerated, safe, and [an] effective option to relieve symptoms, mainly: seizures, tics, depression, restlessness, and rage attacks.” 
Yet another Israeli trial completed the same year similarly reported that the use of CBD extracts resulted in “overall improvements” in a cohort of 53 children with ASD. 
In 2020, US researchers affiliated with Tufts University in Boston reported on their clinical experience working with children and young adults with ASD who had consumed either cannabis or hemp-based products. Among subjects with ASD-associated aggression, 60 percent reported improvements following treatment. Among subjects diagnosed with both ASD and epilepsy, 91 percent reported some improvement in seizure control. 
The following year, Canadian researchers documented the successful treatment of a 15-year-old patient with autism after adding low doses of CBD/THC extracts adjunctively. Researchers reported that the patient’s symptoms improved within six months of treatment, and that he had experienced “positive effects on his behavioral symptoms, anxiety, sleep, and social deficits” since that time. 
Most recently, a placebo-controlled clinical trial reported that the administration of whole-plant cannabis extracts were safe and effective in a cohort of 150 adolescents with autism. Researchers reported: “In this study, we have demonstrated for the first time in a placebo-controlled trial that cannabinoid treatment has the potential to decrease disruptive behaviors associated with ASD, with acceptable tolerability. … Disruptive behavior on the CGI-I [Clinical Global Impression-Improvement scale] was either much or very much improved in 49 percent [of subjects taking] whole-plant extract versus 21 percent on placebo. Median SRS [Social Responsiveness Scale] Total Score (secondary-outcome) improved by 14.9 [points] on whole-plant extract versus 3.6 points after placebo.” 
A 2021 review of the relevant literature summarized: “Cannabis products [have been demonstrated to] reduce the number and/or intensity of different symptoms, including hyperactivity, attacks of self-mutilation and anger, sleep problems, anxiety, restlessness, psychomotor agitation, irritability, aggressiveness perseverance, and depression. Moreover, they [are associated with an] improvement in cognition, sensory sensitivity, attention, social interaction, and language.” Authors concluded, “Cannabis and cannabinoids may have promising effects in the treatment of symptoms related to ASD, and can be used as a therapeutic alternative in the relief of those symptoms.” 
 Zamberletti et al. 2017. The endocannabinoid system and autism spectrum disorders: Insights from animal models. International Journal of Molecular Sciences 18: 1916 [open access journal].
 da Silva et al. 2021. Cannabis and cannabinoid use in autism spectrum disorder: A systematic review. Trends in Psychiatry and Psychotherapy [open access journal].
 Mostafavi and Gaitanis. 2020. Autism spectrum disorder and medical cannabis: Review and clinical experience. Seminars in Pediatric Neurology 35 [online publication].
Real Life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy
Bar-Lev Schleider, L., Mechoulam, R., Saban, N., Meiri, G., & Novack, V. (2019). Real life experience of medical cannabis treatment in autism: Analysis of safety and efficacy. Scientific Reports, 9, 1-7. doi:10.1038/s41598-018-37570-y
Reviewed by Nyasia Sanchez, Masters Candidate, and Frank R. Cicero, PhD, BCBA, LBA, Assistant Professor, Seton Hall University
Why research this topic?
There has been some recent literature suggesting that CBD-enriched cannabis has beneficial effects for individuals with autism spectrum disorder (ASD). Cannabidiol (CBD) is a natural compound found in the cannabis sativa plant. Unlike tetrahydrocannabinol (THC), another compound also found in the cannabis sativa plant, CBD is not associated with the sensation of a “high” or hallucinations when ingested (https://www.healthline.com/health/cbd-vs-thc#chemical-structure). Bar-Lev Schleider et al. (2019), cite past research indicating that CBD may alleviate symptoms of psychosis and anxiety, facilitate REM sleep, and suppress seizures. In 2014, the Israeli Ministry of Health approved the use of CBD-enriched cannabis for the treatment of epilepsy. Parents of children with autism began to seek CBD-enriched cannabis after seeing reductions of anxiety, aggression, panic, tantrums, and self-injury in children with epilepsy receiving the treatment. Although there may be some preliminary evidence of the beneficial effects of CBD treatment for children with ASD, there is a lack of research regarding specific symptoms that are likely to respond to treatment as well as a lack of knowledge regarding safety precautions when using CBD-enriched cannabis with this population.
What did the researchers do?
The purpose of the study was to investigate the general effectiveness and side effects of cannabis treatment with children with ASD. Participants consisted of 188 children with a diagnosis of ASD established per diagnostic standards in Israel. Mean age at start of treatment was 12.9 years with a range of <5 to 18 years. Out of the 188 participants, 27 had a comorbid diagnosis of epilepsy and seven had a comorbid diagnosis of attention deficit hyperactivity disorder. At intake, the use of antipsychotic medications was reported by 56.9% of participants, antiepileptics by 26% of participants, hypnotics and sedatives by 14.9% of participants, and antidepressants by 10.6% of participants. Use of these medications continued throughout the study as needed. A range of pre-existing symptoms was noted in baseline, the most common being restlessness (reported by 90.4% of participants), rage attacks (reported by 79.8% of participants), and agitation (reported by 78.7% of participants). For the majority of participants, treatment consisted of the application of cannabis oil under the tongue, three times per day. The oil consisted of 30% CBD and 1.5% THC on average. A small percentage of participants received slightly modified treatment regimens (i.e. different dosage, different CBD/THC ratio, taking additional doses of CBD for conditions such as insomnia, etc.). Parents of participants completed symptom questionnaires after one and six months of treatment.
What did the researchers find?
Of the 188 original participants, 179 continued with active treatment. At one month follow up, 119 participants completed symptom questionnaires. Data at one month indicated that 48.7% of participants reported significant improvement, 31.1% moderate improvement, and 14.3% no improvement. The presence of side effects was reported by 5.9% of participants. The most common reported side effects at one month included sleeplessness, bad taste and smell of the oil, restlessness, reflux, and lack of appetite. After six months, 155 participants were still in active treatment with 93 completing the symptom questionnaire. Data at six months indicated that 30.1% reported significant improvement, 53.7% moderate improvement, 6.4% slight improvement, and 8.6% no improvement. Reports indicated an improvement in restlessness in 91% of participants and an improvement in rage attacks in 90.3% of participants. The presence of side effects at six months was reported by 25.2% of participants, with the most common side effects being restlessness, sleepiness, psychoactive effects, increased appetite, digestion problems, dry mouth, and lack of appetite. In addition to the symptom questionnaire, reports of “quality of life” and the ability to complete activities of daily living were collected at baseline and at six months. Results indicated statistically significant improvements in “quality of life,” “positive mood,” independent dressing, independent showering, sleeping, and concentration. Improvements were also noted in seizure activity. Out of 13 participants with a diagnosis of epilepsy, 11 reported the disappearance of seizures at six months of treatment, and an additional two reported decreases in seizure activity.
What were the strengths and limitations of the study? What do the results mean?
According to the authors, results of the study show that CBD-enriched cannabis treatment of ASD can potentially lead to improvements in behavioral symptoms. This is consistent with the results of some studies showing improvements in participants with anxiety disorders and other conditions when CBD-enriched treatment was initiated. The authors state that the treatment appears to be safe, well tolerated, and accompanied by notable, yet only minor side effects.
There are, however, a number of significant limitations with the study design and procedures that indicate the need for caution when interpreting the results. First, the study did not contain a comparison control group, therefore no causality between cannabis treatment and behavioral improvement could be established. This indicates that, although improvement was reported in behavioral symptoms, the data may be reflecting the effects of something other than the cannabis treatment. Second, parents seeking cannabis treatment may not represent the majority of families with a child with ASD. It is important to note that 10% of participants reported that they had already used cannabis treatment prior to the present study. This self-selection bias could have affected the results. Third, ASD diagnoses were not confirmed at the time of the study, therefore accuracy in diagnosis cannot be confirmed. Fourth, results were based on subjective completion of questionnaires by parents. Objective measures of behavioral improvement, based on direct observation, were not used. This could have inflated positive results due to parent expectations. In addition, terminology used in the rating scales were sometimes vague and not well defined. Fifth is the limitation of concomitant use of other medications for behavioral and medical treatment. The effects of these medications cannot be teased out from effects of the cannabis treatment. Sixth is the slight variations in treatment regimens and the lack of oversight over treatment fidelity. The final limitation is the large attrition rate from intake to follow up. Out of the 188 participants that started treatment, only 93 participants (49%) remained with the study to the follow up survey.
What do the results mean?
Results indicate that cannabis as a treatment for ASD may potentially be a well-tolerated, safe, and effective option for the treatment of some ASD symptoms including improvements in seizures, tics, depression, rage attacks, and restlessness. Improvements may also be obtained in quality of life and independence in daily living. We do not yet, however, know the mechanisms by which cannabis treatment may show these effects. Unfortunately, a number of significant limitations with the study design prevented a causal relationship from being established between cannabis treatment and behavioral reports. Results having been based on subjective measures are also problematic. Therefore, the results of the current study, although promising, can be considered preliminary at best. The authors suggest that a call for a double-blind, placebo-controlled clinical trial is indicated. In the meantime, extreme caution and professional consultation should be used when considering cannabis treatment for individuals with autism.